1. Different target cell- and signalling pathway-specificity was shown for the epidermal growth factor receptor (EGFR) and the receptor-like gpl85erbB-2, a molecule related to, but distinct from, the EGFR. The domain responsible for this specificity (and likely for specific binding of intracellular substrates) was localized to a 150-amino acid stretch encompassed in the tyrosine kinase (TK) region and immediately adjacent to the transmembrane (TM) region. Discrete amino acid deletions in this region of the EGFR yielded a mutant which had lost its mitogenic ability albeit retaining its kinase activity. 2. The mitogenic signalling pathways underlying the action of EGFR and erbB-2 have been studied. Both EGFR and gpl85erbB-2 can phosphorylate phospholipase C-gamma (PLC-gamma) and the p2lras GTPase activating protein (GAP), thus showing coupling with these two pathways. However, the distinct signalling specificity of EGFR and erbB-2 was not accounted for by any difference in coupling with PLC-gamma/phosphatidyl inositol bisphosphorylate (PIP 2) turnover of p2lras/GAP signalling. Therefore, novel substrates for these two kinases are being isolated and characterized at present. 3. The mechanisms of oncogenic activation of gpl85erbB-2 have been investigated. Results showed that at variance with other growth factor receptors. gpl85erbB-2 acts as a kinase (under conditions of overexpression) in the absence of ligand stimulation. This activation does not appear to require intermolecular allosteric cooperation between gpl85erbB-2 molecules.